All publications cited herein are incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. The following description includes information that may be useful in understanding the present subject matter. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed subject matter, or that any publication specifically or implicitly referenced is prior art.
Magnetic resonance imaging (“MRI”) is a commonly-accepted technique used in medical imaging to visualize the structure and function of the body and provide detailed images in any plane. In MRI, a scanner creates a powerful magnetic field which aligns the magnetization of hydrogen atoms in a biological subject. Radio waves are used to alter the alignment of this magnetization, causing the hydrogen atoms to emit a weak radio signal which is amplified by the scanner. This technology is useful in connection with disease diagnosis and prognosis, and in the broader study of biological systems. Indeed, many hospitals and medical facilities have MRI imaging equipment on-site, and routinely make use of it to aid in the diagnosis and monitoring of an array of diseases and physiologic conditions. However, as MRI technology has progressed very little there remains a strong need in the art for improvements in MRI methods and apparatus, specifically improvements in image quality and reproducibility.
Several promising methods of improving nuclear magnetic resonance (“NMR”) signal, including high field, rapid gradients, parallel radio frequency (R.F. or r.f.) excitation and acquisition, super-cooled R.F.-coils, rapid imaging and magnetization transfer sequences, as well as paramagnetic contrast agents, have been proposed and researched. However, these methods all operate within the constraints of Boltzman distribution and therefore can only provide incremental improvements in the signal to noise ratio (“SNR”) in MRI, varying from 2-10 fold [J. H. Gillard, A. D. Waldman, and P. B. Barker, Clinical MR Neuroimaging: Diffusion, Perfusion and Spectroscopy, Cambridge University Press, New York, N.Y., 2005].
However, a family of hyperpolarization techniques exist which address the issue of low SNR by developing polarization several orders of magnitude greater than that predicted in the Boltzman equation, and by using a variety of physical and chemical methods to approach polarization of unity (P=100%). Hyperpolarized noble gas imaging has been practiced by scientists and clinicians for over ten years with great success. The use of xenon gas has been in use by clinicians for two or more years [M. S. Albert, G. D. Cates, B. Driehuys, W. Happer, B. Saam, C. S. Springer, and A. Wishnia, Biological Magnetic-Resonance-Imaging Using Laser Polarized Xe-129. Nature 370 (1994) 199-201]. Hyperpolarized heteronuclear NMR with 13C and 15N became available for in vivo applications through the systematic improvement and exploitation of dynamic nuclear polarization (“DNP”) [J. H. Ardenkjaer-Larsen et al., Increase in signal-to-noise ratio of >10,000 times in liquid-state NMR. Proceedings of the National Academy of Sciences of the United States of America 100 (2003) 10158-10163] and parahydrogen-induced polarization (“PHIP”) [C. R. Bowers, and D. P. Weitekamp, Para-Hydrogen and Synthesis Allow Dramatically Enhanced Nuclear Alignment. Journal of the American Chemical Society 109 (1987) 5541-5542]. U.S. Pat. No. 6,574,495 to Golman et al., and U.S. Pat. No. 6,872,380 to Axelsson et al., describe apparatus and processes for using PHIP, which is also known as PASADENA (parahydrogen and synthesis allow dramatically enhanced nuclear alignment).
Although PASADENA provides much needed improvement in MRI technology, PASADENA is only utilized in a few laboratories. Cost factors combined with the operational complexity of current PASADENA apparatus have proven problematic in advancing the technique, which has lead to secondary disadvantages including lack of multi-site comparisons and limiting studies to improve on and examine the merits of PASADENA, handicapping further development and propagation of the technique. Commercial devices based on DNP are available; however, the efficiency of such machines is less than ideal. For example, it takes as long as 90 minutes to complete a cycle using a DNP-based device.
The present subject matter is written to overcome this barrier by describing construction of a simple PASADENA polarizer which will provide low-cost access to PASADENA hyperpolarization, allow a systematic comparison between DNP and PASADENA and encourage avenues which appear to offer great promise for in vivo hyperpolarized MRI studies not readily amenable to DNP or hyperpolarized noble gases. In addition, the subject matter describes methods for installing, calibrating and operating the polarizer to optimize PASADENA hyperpolarization. While the ground breaking early discoveries, and some of the subsequent advancements in PASADENA method [Kuhn L. T., Bargon J., Transfer of parahydrogen-induced hyperpolarization to heteronuclei. Top Curr Chem 276: (2007) 25-68] required only an NMR spectrometer, an unsaturated molecule and a supply of parahydrogen gas, levels of hyperpolarization reported were generally around 1%, which are insufficient for biological, pre-clinical or clinical studies. Accordingly, a polarizer interface is needed to allow for rapid mixing and chemical reaction of parahydrogen, 13C (or 15N) enriched precursor in a catalyst solution under the correct conditions, within a low field NMR unit. The high spin order inherent in parahydrogen is quantitatively transferred to the precursor, with subsequent generation of the hyperpolarized 13C imaging reagent for injection into an animal or biological test system held within a conventional NMR spectrometer.
With the present apparatus, high levels of hyperpolarization permitted early in vivo studies, which proved the potential of hyperpolarized 13C MRI in biology [Golman K. et al., Parahydrogen-induced polarization in imaging: subsecond C-13 angiography. Magn Reson Med 46: (2001) 1-5]. Ideally, and within a few minutes, the process is repeated, with the same or very comparable volume and hyperpolarization of the product. The PASADENA polarizer described herein advances upon the prototype described briefly by Axelsson et al. [Golman K. et al., Parahydrogen-induced polarization in imaging: subsecond C-13 angiography. Magn Reson Med 46: (2001) 1-5] (GE/Amersham, Malmö, Sweden). It is designed to be reliable, low cost and to produce hyperpolarized biomolecules in solution quickly and efficiently in amounts applicable for biological use. Additionally, unlike previous polarizers, which required the constant attention of 4-5 dedicated and highly trained individuals and was variable in its performance, a single person can operate the subject matter apparatus after a single demonstration. Combined with Quality Assurance (“QA”) methods, described herein, the subject matter PASADENA polarizer and methods for using such are shown to provide reproducible hyperpolarization of biomolecules at P=[15.3±1.9]%, where P stands for a polarization rate.